In a study reported in JAMA Oncology, Pearlman et al found that 16% of patients with early-onset colorectal cancer had germline cancer susceptibility mutations, with a wide array of such mutations being identified. Heather Hampel, MS, CGC, of The Ohio State University Comprehensive Cancer Center, is the corresponding author of the JAMA Oncology article.

The study involved 450 patients diagnosed with colorectal cancer at age < 50 years from 51 hospitals in the Ohio Colorectal Cancer Prevention Initiative from January 2013 to June 2016. Mismatch repair deficiency was assessed by microsatellite instability and/or immunohistochemistry, and germline DNA was assessed for 25 mutations by next-generation sequencing.

Prevalence and Types

Overall, 75 mutations were found in 72 patients (16%). A total of 48 (10.7%) had mismatch repair–deficient tumors, with 40 of them (83.3%) having at least 1 gene mutation. A total of 37 had Lynch syndrome, 13 with MLH1 (including 1 with constitutional MLH1 methylation), 16 with MSH2, 1 with MSH2/monoallelic MUTYH, 2 with MSH6, and 5 with PMS2. One patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant. Nine patients had double somatic mismatch repair mutations, including two with germline biallelic MUTYH mutations and one with somatic MLH1 methylation.

A total of 402 patients (89.3%) had mismatch repair–proficient tumors, with 32 (8%) having at least 1 mutation. Of them, nine had mutations in high-penetrance colorectal cancer genes (APC in five, APC/PMS2 in one, biallelic MUTYH in two, and SMAD4 in one). Mutations in high- or moderate-penetrance genes not typically associated with colorectal cancer were identified in 13 (ATM in 3, ATM/CHEK2 in 1, BRCA1 in 2, BRCA2 in 4, CDKN2A in 1, and PALB2 in 2). Mutations in low-penetrance colorectal cancer genes were found in 10 patients (APC c.3920T>A, p.I1307K in 3 and monoallelic MUTYH in 7).

The investigators noted that 24 of 72 patients (33.3%) who tested positive for mutations did not meet established genetic testing criteria for the gene with the mutation.

The investigators concluded: “Of 450 patients with early-onset [colorectal cancer], 72 (16%) had gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and testing with a multigene panel could be considered for all patients with early-onset [colorectal cancer].”